Abstract Covalent post-translational modifications (PTMs) of histone proteins are widely believed to facilitate epigenetic inheritance of gene expression information from one cell generation to the next. However, this premise has not been directly tested in animals, limiting our understanding of the contribution of PTMs to complex molecular or developmental processes that underlie human disease. To interrogate this relationship, we have developed a genetic strategy in Drosophila melanogaster for replacement of the endogenous histone gene cluster with an engineered multigene array of the five core histone subunits with specific mutations in modifiable residues. Methylation of lysine 36 in the histone H3 subunit (H3K36) is a transcription-linked PTM that has well- characterized roles in suppression of cryptic initiation and regulation of alternative splicing, making it an attractive choice for study using our system. We aim to use H3K36 mutant models to evaluate the contribution of H3K36 methylation to proper proliferation and development. Additionally, we aim to directly test the molecular requirement for H3K36 methylation in proper regulation of global gene expression and alternative splicing, and to correlate molecular role with observed cellular and developmental phenotypes. These studies will be the first to directly test the interplay between molecular mechanisms in which H3K36 methylation takes a part and cellular and developmental processes that are relevant to disease.